medwireNews: CheckMate 012 trial results suggest that nivolumab may have potential as a first-line treatment for patients with stage IIIB or IV non-small-cell lung cancer (NSCLC), alone or in combination with platinum doublet chemotherapy.

The first of the two reports from the phase I study, both published in the Journal of Clinical Oncology, describes the programmed death-1 immune checkpoint inhibitor monotherapy as having “a tolerable safety profile and durable responses”.

The majority (71%) of the 52 patients given nivolumab at a dose of 3 mg/kg every 2 weeks until progression or onset of intolerable side effects experienced treatment-related side effects, most commonly fatigue, rash, nausea, diarrhoea, pruritus and arthralgia, say Scott Gettinger, from Yale Cancer Center in New Haven, Connecticut, USA, and co-authors.

Grade 3–4 adverse events occurred in 19% of patients but rash was the only recurring side effect, affecting two individuals, and there were no treatment-related deaths.

Median progression-free survival (PFS) was 3.6 months, with a PFS rate after 24 weeks of 41%, prompting the authors to conclude that first-line nivolumab for advanced NSCLC showed “promising activity with a manageable safety profile”.

In the second report, Naiyer Rizvi, from Columbia University Medical Center in New York, USA, and team say that the safety profile of nivolumab plus platinum-based doublet therapy (PT-DC) was "consistent with that expected for individual agents", albeit with a higher rate of discontinuation than that seen for single therapies alone.

The team assigned 56 patients with treatment-naive advanced NSCLC to receive four cycles of one of four regimes followed by nivolumab monotherapy until progression or intolerable toxicity. These were: nivolumab 5 mg/kg or 10 mg/kg every 3 weeks plus paclitaxel
–carboplatin
for any histology; nivolumab 10 mg/kg every 3 weeks alongside gemcitabine
–cisplatin
for patients with squamous disease; and pemetrexed
–cisplatin for patients with nonsquamous NSCLC.

Although there were no dose-limiting toxicities in the first 6 weeks of treatment, 95% of patients reported side effects and 45% experienced grade 3–4 side effects, including pneumonitis in four patients.

Treatment-related side effects led to 21% of the patients discontinuing treatment, with grade 3–4 pneumonitis and acute renal failure each cited in three patients. Ten of the 12 discontinuations occurred during the maintenance monotherapy.

Discontinuation rates varied from 8% of the patients given the nivolumab 10 mg/kg plus gemcitabine–cisplatin regimen to 33% of the patients who received nivolumab 10 mg/kg plus pemetrexed–cisplatin, the researchers note.

Not considering tumour PD-L1 expression, the best objective response rate, including only patients with a partial or complete response ranged from 33% to 47%, with the best rate, including one complete response, achieved in a patient treated with nivolumab 10 mg/kg with gemcitabine–cisplatin. Including patients with stable disease, the objective response rate increased by 27% to 58%.

The median PFS was 4.8 months in the patients given nivolumab 10 mg/kg with paclitaxel–carboplatin, 5.7 months for those given 10 mg/kg plus gemcitabine–cisplatin, 6.8 months for those given 10 mg/kg with pemetrexed–cisplatin and 7.1 months for those given nivolumab 5 mg/kg plus paclitaxel–carboplatin.

The 24-week PFS mark was achieved by 38%, 51%, 71% and 51% of the groups, respectively.

"Despite the small sample sizes of the individual cohorts and patient selection for phase I studies, the clinical activity of nivolumab plus PT-DC, and of nivolumab 5 mg/kg plus paclitaxel-carboplatin in particular, is promising relative to historical results with PT-DC alone", Naiyer Rizvi et al conclude.